In situ forming implants and microparticles for intraarticular drug delivery

Abstract

Implants and microparticles for intraarticular drug delivery are provided herein. The implants and microparticles can be formed in situ in a joint for sustained drug delivery, for example for the treatment of osteoarthritis. Methods of treating osteoarthritis are also provided.

1 . A method of forming an implant, the method comprising:
 providing a mixture comprising
 a water-miscible organic solvent; 
 a water-immiscible organic solvent; 
 a biodegradable polyester comprising poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof; and 
 a disease-modifying osteoarthritis drug; and 
   contacting the mixture with an aqueous environment to form a precipitate from the mixture to provide the implant.   
     
     
         2 . The method of  claim 1 , wherein
 the water-miscible organic solvent comprises N-methyl-2-pyrrolidone, and   the water-immiscible organic solvent comprises benzyl benzoate, benzyl alcohol, or a combination thereof.   
     
     
         3 . The method of  claim 1 , wherein the biodegradable polyester comprises poly(lactic-co-glycolic acid) having a lactide: glycolide ratio of 25:75 to 75:25. 
     
     
         4 . The method of  claim 1 , wherein the mixture comprises N-methyl-2-pyrrolidone, benzyl benzoate, and benzyl alcohol, and a weight ratio of N-methyl-2-pyrrolidone:benzyl benzoate:benzyl alcohol is 10-30:30-50:30-50. 
     
     
         5 . The method of  claim 3 , wherein the poly(lactic-co-glycolic acid) is present in an amount of 15 to 30 weight percent, based on the total weight of the mixture. 
     
     
         6 . The method of  claim 3 , wherein the poly(lactic-co-glycolic acid) is present in an amount of 20 to 25 weight percent, based on the total weight of the mixture. 
     
     
         7 . The method of  claim 1 , wherein the disease-modifying osteoarthritis drug is punicalagin. 
     
     
         8 . The method of  claim 1 , wherein the contacting comprises injecting the mixture intraarticularly, and the implant is formed in situ in a joint. 
     
     
         9 . The method of  claim 1 , wherein less than 25% of the disease-modifying osteoarthritis drug in the implant is released from the implant after 15 days in an aqueous environment. 
     
     
         10 . An implant for intraarticular drug delivery made by the method of  claim 1 . 
     
     
         11 . A method of forming a plurality of microparticles, the method comprising:
 combining
 a biodegradable polyester comprising poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof; and 
 a disease-modifying osteoarthritis drug, 
   in a solvent to provide a first phase;   combining the first phase with a second phase comprising an oil to provide an emulsion, wherein the first phase is a minor phase and the second phase is a major phase; and   contacting the emulsion with an aqueous environment to precipitate the plurality of microparticles from the emulsion.   
     
     
         12 . The method of  claim 11 , wherein the disease-modifying osteoarthritis drug is punicalagin. 
     
     
         13 . The method of  claim 11 , wherein the oil comprises sesame oil. 
     
     
         14 . The method of  claim 11 , wherein the biodegradable polyester comprises poly(lactic-co-glycolic acid) having a lactide:glycolide ratio of 25:75 to 75:25. 
     
     
         15 . The method of  claim 11 , wherein the first phase further comprises sucrose acetate isobutyrate. 
     
     
         16 . The method of  claim 11 , wherein the contacting comprises injecting the mixture intraarticularly, and the microparticles are formed in situ in a joint. 
     
     
         17 . A plurality of microparticles comprising a biodegradable polyester comprising poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof, and a disease-modifying osteoarthritis drug, wherein the plurality of microparticles are made by the method of  claim 11 . 
     
     
         18 . A method of treating osteoarthritis by intraarticular injection of punicalagin. 
     
     
         19 . The method of  claim 18 , wherein the punicalagin is disposed in an implant comprising a biodegradable polyester comprising poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof for intraarticular drug delivery. 
     
     
         20 . The method of  claim 18 , wherein the punicalagin is disposed in a plurality of microparticles comprising a biodegradable polyester comprising poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof for intraarticular drug delivery.